EP3389062B1 - Method for producing superparamagnetic nanocomposite and superparamagnetic nanocomposite produced using same - Google Patents
Method for producing superparamagnetic nanocomposite and superparamagnetic nanocomposite produced using same Download PDFInfo
- Publication number
- EP3389062B1 EP3389062B1 EP17841647.5A EP17841647A EP3389062B1 EP 3389062 B1 EP3389062 B1 EP 3389062B1 EP 17841647 A EP17841647 A EP 17841647A EP 3389062 B1 EP3389062 B1 EP 3389062B1
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- EP
- European Patent Office
- Prior art keywords
- superparamagnetic nanocomposite
- superparamagnetic
- nanocomposite
- magnetic
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002114 nanocomposite Substances 0.000 title claims description 148
- 238000004519 manufacturing process Methods 0.000 title claims description 33
- 230000005291 magnetic effect Effects 0.000 claims description 30
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000002159 nanocrystal Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 18
- 239000002798 polar solvent Substances 0.000 claims description 16
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000007942 carboxylates Chemical class 0.000 claims description 12
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 12
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 12
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012692 Fe precursor Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- -1 poly(ethylene glycol) Polymers 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 9
- 239000003381 stabilizer Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 229910001868 water Inorganic materials 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229960002089 ferrous chloride Drugs 0.000 claims description 6
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 6
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 6
- 229940044631 ferric chloride hexahydrate Drugs 0.000 claims description 5
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical group O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229940032296 ferric chloride Drugs 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- PQUXFUBNSYCQAL-UHFFFAOYSA-N 1-(2,3-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1F PQUXFUBNSYCQAL-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 229910002554 Fe(NO3)3ยท9H2O Inorganic materials 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N Tetraethylene glycol, Natural products OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 2
- SZQUEWJRBJDHSM-UHFFFAOYSA-N iron(3+);trinitrate;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O SZQUEWJRBJDHSM-UHFFFAOYSA-N 0.000 claims description 2
- 229940047670 sodium acrylate Drugs 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 description 30
- 210000003743 erythrocyte Anatomy 0.000 description 21
- 238000005259 measurement Methods 0.000 description 19
- 238000007885 magnetic separation Methods 0.000 description 14
- 238000009826 distribution Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 10
- 238000002955 isolation Methods 0.000 description 8
- 230000005415 magnetization Effects 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 239000002122 magnetic nanoparticle Substances 0.000 description 7
- 239000006249 magnetic particle Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000005389 magnetism Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012620 biological material Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 229910052779 Neodymium Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflonยฎ Polymers 0.000 description 2
- 238000004873 anchoring Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000003302 ferromagnetic material Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000696 magnetic material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000013077 target material Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalanยฎ Polymers 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005307 ferromagnetism Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
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- 230000035484 reaction time Effects 0.000 description 1
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- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
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Images
Classifications
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F41/00—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties
- H01F41/02—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets
- H01F41/0206—Manufacturing of magnetic cores by mechanical means
- H01F41/0246—Manufacturing of magnetic circuits by moulding or by pressing powder
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/01—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials
- H01F1/03—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity
- H01F1/12—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials
- H01F1/34—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials non-metallic substances, e.g. ferrites
- H01F1/342—Oxides
- H01F1/344—Ferrites, e.g. having a cubic spinel structure (X2+O)(Y23+O3), e.g. magnetite Fe3O4
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
- B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
- B82B1/008—Nanostructures not provided for in groups B82B1/001ย -ย B82B1/007
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
- B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
- B82B3/0009—Forming specific nanostructures
- B82B3/0038—Manufacturing processes for forming specific nanostructures not provided for in groups B82B3/0014ย -ย B82B3/0033
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G49/00—Compounds of iron
- C01G49/02—Oxides; Hydroxides
- C01G49/08—Ferroso-ferric oxide (Fe3O4)
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/0036—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity
- H01F1/0045—Zero dimensional, e.g. nanoparticles, soft nanoparticles for medical/biological use
- H01F1/0054—Coated nanoparticles, e.g. nanoparticles coated with organic surfactant
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/01—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials
- H01F1/03—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity
- H01F1/12—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials
- H01F1/14—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials metals or alloys
- H01F1/20—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials metals or alloys in the form of particles, e.g. powder
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/30—Three-dimensional structures
- C01P2002/32—Three-dimensional structures spinel-type (AB2O4)
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/03—Particle morphology depicted by an image obtained by SEM
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/50—Agglomerated particles
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/51—Particles with a specific particle size distribution
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/22—Rheological behaviour as dispersion, e.g. viscosity, sedimentation stability
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/42—Magnetic properties
Definitions
- the present invention relates to a method of manufacturing a superparamagnetic nanocomposite and a superparamagnetic nanocomposite manufactured using the same, and more particularly to a method of manufacturing a superparamagnetic nanocomposite suitable for use in the detection of a target biomaterial and a superparamagnetic nanocomposite manufactured using the same.
- a biomolecule such as a target biomarker
- a binding assay based on an antigen-antibody immunoreaction, a DNA hybridization, a receptor reaction or the like, depending on the type of target material, and the presence of a target molecule is determined by means of a signal transducer that converts the binding event with the target molecule into a measurable signal.
- a magnetic nanoparticle mediated isolation technique using magnetic force in the binding assay is advantageous because a target biomolecule is obtained in isolation from a suspended solution comprising various impurities or non-target materials, which are mixed together, through a concentrating process (positive isolation) or by removing non-target molecules (negative isolation), thus exhibiting a simplified assay, processing feasibility, high sensitivity, improved specificity, high-throughput screening, and scalability.
- a magnetic nanoparticle mediated isolation technique is performed in a manner in which a ligand material that specifically binds to the target molecule is attached to particles, followed by recognizing and bonding of the ligand material to the target molecule in the mixed solution and separation of the magnetic particles using external magnetic force.
- magnetic particles suitable for use in a target molecule sensing platform, are required to (i) minimize non-specific adsorption from a variety of non-specific materials in a suspended solution, (ii) maintain the stability of colloidal particles from various biochemical environments, and (iii) facilitate surface bonding of various functional groups.
- the particles are preferably hydrophilic and neutral and contain hydrogen bond acceptors.
- PEGylation that is, coating the surface of particles with poly(ethylene glycol) which is one of the biocompatible polymer is to date still considered to be the most successful way to design nanoparticles having a non-fouling bio-interface.
- the precisely adsorbed PEG layer satisfies the requirements listed above, reduces non-specific adsorption of particles and increases stability.
- the present inventors provide a method of manufacturing a superparamagnetic nanocomposite, that is, a superparamagnetic iron oxide nanocomposite, suitable for use in magnetic separation for the detection of a target biomaterial.
- the method of manufacturing the superparamagnetic nanocomposite has a higher yield and a high rate without complicated processing than a conventional method of manufacturing a magnetic nanoparticle for magnetic separation and is capable of mass production of the superparamagnetic nanocomposite having excellent properties with uniform size and particle size distribution, high aqueous solution dispersibility and high magnetization and being capable of maintaining superparamagnetism, thereby culminating in the present invention.
- Tang et al discloses superparamagnetic Fe 3 O 4 nanocrystal cluster of 70 to 180 nm using citrates as stabilizer and water as size control agent in ethylene glycol as solvent.
- US2011/0297871A1 discloses composite beads synthesized from FeCl 3 , trisodium citrate, and natrium acetate in ethylene glycol in an autoclave at 200 ยฐC for 12 h.
- Particles of US2016/0122797A1 were synthesized in the presence of diethylene glycol/NaOH after FeCl 3 , polyacrylic acid, diethylene glycol were heated at 220 ยฐC for 30 min. Woo et al.
- the present invention is intended to provide a method of manufacturing a superparamagnetic nanocomposite having a higher yield and a high rate without complicated processing and being capable of mass production of the superparamagnetic nanocomposite having excellent properties with uniform size and particle size distribution, high aqueous solution dispersibility and high magnetization and being capable of maintaining superparamagnetism, and is also intended to provide a superparamagnetic nanocomposite manufactured by the method.
- the present invention provides a method of manufacturing a superparamagnetic nanocomposite, according to claim 1 and superparamagnetic nanocomposite according to claim 11.
- the present invention provides a method of manufacturing a superparamagnetic nanocomposite, comprising: mixing an iron precursor, a solvent, a stabilizing agent and a reducing agent; subjecting a mixed solution in the mixing step to hydrothermal synthesis at a temperature of 150 to 240ยฐC, preferably 200 to 240ยฐC and more preferably 200ยฐC and a pressure of 1.5 to 2.5 bar to synthesize a superparamagnetic nanocomposite in nanocluster form; and separating the synthesized superparamagnetic nanocomposite.
- the method of manufacturing the superparamagnetic nanocomposite according to the present invention may further include washing the separated superparamagnetic nanocomposite with a polar solvent.
- the iron precursor may be selected from the group consisting of ferric chloride hexahydrate (FeCl 3 โ 6H 2 O), ferrous chloride, ferrous chloride tetrahydrate, ferric chloride, and ferric nitrate nonahydrate (Fe(NO 3 ) 3 โ 9H 2 O), and is preferably selected from the group consisting of ferric chloride hexahydrate (FeCl 3 โ 6H 2 O), ferrous chloride, ferrous chloride tetrahydrate, and ferric chloride. More preferably useful is ferric chloride hexahydrate (FeCl 3 โ 6H 2 O).
- the solvent may be selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, and glycerol.
- ethylene glycol Preferably useful is ethylene glycol.
- the stabilizing agent may be a compound having a carboxyl group.
- the stabilizing agent is selected from the group consisting of dicarboxyl poly(ethylene glycol) having a molecular weight of 500 to 50,000, preferably 2000 to 8000, and more preferably 2000 and optionally trisodium citrate dihydrate (HOC(COONa)(CH 2 COONa) 2 โ 2H 2 O; C 6 H 5 Na 3 O 7 ).
- the reducing agent may be selected from the group consisting of sodium acetate, sodium acrylate, urea, sodium formate, and ammonium acetate.
- Preferably useful is sodium acetate.
- the iron precursor and the solvent may be mixed at a molar ratio of 1:10 to 1:300, and preferably 1:40 to 1:200.
- the iron precursor and the stabilizing agent may be mixed at a molar ratio of 1:0.0000013 to 1:1, and preferably 1:0.0000013 to 1:0.8.
- the iron precursor and the reducing agent may be mixed at a molar ratio of 1:1 to 1:20, preferably 1:3 to 1:15, and more preferably 1:7 to 1:15.
- the polar solvent may be selected from the group consisting of ethanol, water, methanol, acetone, liquid ammonia, ethyl acetate, ether, tetrahydrofuran, potassium hydroxide, sodium hydroxide, and dichloromethane.
- separating the synthesized superparamagnetic nanocomposite may be performed using a centrifuge or using magnetism, each of which may be conducted using typically useful methods.
- washing the separated superparamagnetic nanocomposite with the polar solvent may be performed in a manner in which the superparamagnetic nanocomposite, separated during separating the synthesized superparamagnetic nanocomposite, is washed with a polar solvent to remove impurities, whereby the superparamagnetic nanocomposite is imparted with high stability and uniform particle distribution.
- the polar solvent may include any one selected from among ethanol, alcohol, liquid ammonia, acetone, methanol, chloroform, ethyl acetate, ether, tetrahydrofuran, potassium hydroxide, sodium hydroxide, dichloromethane, and water.
- washing the separated superparamagnetic nanocomposite with a polar solvent is preferably performed three times.
- the number of washing processes is not limited to 3, but the washing process may be conducted once or several times, and such simple modification of the number of washing processes may fall within the scope of the present invention.
- the superparamagnetic nanocomposite may be manufactured without performing washing the separated superparamagnetic nanocomposite with the polar solvent, but in order to exhibit high stability and uniform particle distribution as described above, the separated superparamagnetic nanocomposite is preferably washed with the polar solvent. Washing the separated superparamagnetic nanocomposite with the polar solvent may be performed using any one among typically useful methods. Here, washing the separated superparamagnetic nanocomposite with the polar solvent may be conducted using a centrifuge, which is one among typically useful methods, and achieving both separation and washing of the superparamagnetic nanocomposite during separating the synthesized superparamagnetic nanocomposite may fall within the scope of the present invention. This is because separating the synthesized superparamagnetic nanocomposite may be carried out separately through primary and secondary procedures and the like and may include separation and washing together.
- washing the separated superparamagnetic nanocomposite with the polar solvent may include washing the separated superparamagnetic nanocomposite with an ethanol solvent and washing the superparamagnetic nanocomposite, washed with the ethanol solvent, with a water solvent.
- the washing process using the ethanol solvent is performed using an ethanol solvent, which is a polar solvent that facilitates the dissolution of a solvent and a reducing agent, whereby the ultimately obtained superparamagnetic nanocomposite may have favorable properties such as surface charge and the like.
- washing the superparamagnetic nanocomposite, already washed with the ethanol solvent, with the water solvent is favorable because dispersion in a deionized water aqueous solution can be achieved, making it possible to realize magnetic separation for the detection of a target biomaterial.
- the dispersibility of the superparamagnetic nanocomposite in an aqueous solution may be adjusted using the carboxylate (COO - ) group of the stabilizing agent.
- the superparamagnetic nanocomposites have a diameter of 100 nm to 350 nm.
- the superparamagnetic nanocomposite preferably has a diameter of 150 nm to 350 nm and more preferably 200 nm to 350 nm.
- the present invention provides a superparamagnetic nanocomposite manufactured by the above method.
- the superparamagnetic nanocomposites have a diameter of 100 nm to 350 nm.
- the superparamagnetic nanocomposite preferably has a diameter of 150 nm to 350 nm, and more preferably 200 nm to 350 nm.
- the superparamagnetic nanocomposite may comprises a magnetic nanocrystal having a diameter of from more than 0 to 10 nm, wherein a surface of the magnetic nanocrystal is stabilized by carboxylate (COO - ) group, wherein the superparamagnetic nanocomposite may have a plurality of magnetic nanocrystals clustered therein, have a nanoclustered shape having a diameter of 100 nm to 350 nm and have hydrophilicity so as to be dispersed in an aqueous solution.
- the superparamagnetic nanocomposites have the nanoclustered shape having a diameter of 100 nm to 350 nm, and more preferably 200 nm to 350 nm.
- the magnetic nanocrystal may be Fe 3 O 4 having a diameter of from more than 0 to 10 nm.
- the present invention provides a superparamagnetic nanocomposite comprising a magnetic nanocrystal which is Fe 3 O 4 having a diameter of from more than 0 to 10 nm, wherein a surface of the magnetic nanocrystal is stabilized by carboxylate (COO - ) group, wherein the superparamagnetic nanocomposite has a plurality of magnetic nanocrystals clustered therein, has a nanoclustered shape having a diameter of 100 nm to 450 nm and has hydrophilicity so as to be dispersed in an aqueous solution.
- the superparamagnetic nanocomposites have the nanoclustered shape having a diameter of 100 nm to 350 nm, and more preferably 200 nm to 350 nm.
- a method of manufacturing the superparamagnetic nanocomposite has a higher yield and a high rate without complicated processing than a conventional method of manufacturing a magnetic nanoparticle for magnetic separation and is capable of mass production of the superparamagnetic nanocomposite having excellent properties with uniform size and particle size distribution, high aqueous solution dispersibility and high magnetization and being capable of maintaining superparamagnetism. Because a superparamagnetic nanocomposite manufactured by the method have high magnetization and is capable of maintaining superparamagnetism superparamagnetism, the superparamagnetic nanocomposite can be utilized in magnetic separation for the detection of a target biomaterial.
- a superparamagnetic nanocomposite refers to superparamagnetic particles having nanoclustered shape having a diameter of 100 to 350 nm, preferably 150 to 350 nm, and more preferably 200 to 350 nm configured such that single magnetic particles having a diameter of several nanometer (a diameter of from more than 0 to 10 nm), that is, magnetic nanocrystals, are clustered therein.
- room temperature may refer to, but is not limited to, 15 to 25ยฐC, which enables the most easily practicable reaction by a worker because increasing or decreasing the temperature is not necessary. Depending on the surrounding conditions and environments, the same may be a temperature higher or lower than the above range.
- superparamagnetism is a property that may be controlled using a magnetic force and enables re-dispersion in the absence of a magnetic force, and a superparamagnetic nanocomposite may be utilized in diverse fields requiring magnetic nanoparticles having superparamagnetism.
- a superparamagnetic nanocomposite (particularly a superparamagnetic iron oxide nanocomposite) having magnetic nanoclustered shape of Example 1 was synthesized using a method shown in FIG. 1 .
- the stirred mixture was placed in a Teflon tube for hydrothermal synthesis, enveloped with a stainless steel container so as to be hermetically sealed, placed in a hydrothermal synthesizer, heated from room temperature to 200ยฐC at a rate of 7 ยฐC/min, and reacted at 200ยฐC for 8 hr to 12 hr while maintaining the temperature at 200ยฐC.
- the inner pressure of the sealed synthesis tube was maintained at 1.5 to 2.5 bar.
- the supernatant was removed through magnetic separation, and the synthesized particles were washed with 30 mL of ethanol five times and deionized water five times and then dried, thus yielding a superparamagnetic nanocomposite.
- the magnetic separation was performed in a manner in which a sample was placed on a neodymium permanent magnet and particles were collected to thereby remove the supernatant, thus separating the particles.
- the synthesized particles may also be separated through centrifugation.
- magnetic nanocrystals that is, magnetite nanocrystals configured such that the surface thereof is stabilized by the carboxylate (COO - ) group of the trisodium citrate dihydrate molecule (i.e. by chemisorbing or anchoring the carboxylate (COO - ) group of the trisodium citrate dihydrate molecule and the Fe-OH group) were formed, and the particles were negatively charged by the carboxylate (COO - ) group of the trisodium citrate dihydrate molecule to thus cause electrostatic repulsion, and were thus stabilized. Meanwhile, surface tension simultaneously acted in the clustering direction, thereby decreasing the high surface energy of the magnetic nanocrystals, and a superparamagnetic nanocomposite having a uniform size was formed through the balance of electrostatic repulsion and surface tension.
- a superparamagnetic nanocomposite (particularly a superparamagnetic iron oxide nanocomposite) having magnetic nanoclustered shape of Example 1 was synthesized using a method shown in FIG. 1 .
- the stirred mixture was placed in a Teflon tube for hydrothermal synthesis, enveloped with a stainless steel container so as to be hermetically sealed, placed in a hydrothermal synthesizer, heated from room temperature to 200ยฐC at a rate of 7 ยฐC/min, and reacted at 200ยฐC for 8 hr to 12 hr while maintaining the temperature at 200ยฐC.
- the inner pressure of the sealed synthesis tube was maintained at 1.5 to 2.5 bar.
- the supernatant was removed through magnetic separation, and the synthesized particles were washed with 30 mL of ethanol five times and deionized water five times and then dried, thus yielding magnetic nanoparticles.
- the magnetic separation was performed in a manner in which a sample was placed on a neodymium permanent magnet and particles were collected to thereby remove the supernatant, thus separating the particles.
- the synthesized particles may also be separated through centrifugation.
- magnetic nanocrystals that is, magnetite nanocrystals configured such that the surface thereof is stabilized by the carboxylate (COO - ) group of the PEG-diacid molecule (i.e. by chemisorbing or anchoring the carboxylate (COO - ) group of the PEG-diacid molecule and the Fe-OH group) were formed, and the particles were negatively charged by the carboxylate (COO - ) group of the PEG-diacid molecule to thus cause electrostatic repulsion, and were thus stabilized. Meanwhile, surface tension simultaneously acted in the clustering direction, thereby decreasing the high surface energy of the magnetic nanocrystals, and a superparamagnetic nanocomposite having a uniform size was formed through the balance of electrostatic repulsion and surface tension.
- the superparamagnetic nanocomposites of Examples 1 and 2 were observed to determine the size and shape thereof using a SEM (S-4700, Hitachi, Tokyo, Japan). The results are shown in FIG. 2 .
- FIG. 2 shows the results of SEM observation of the superparamagnetic nanocomposites of Examples 1 and 2.
- Example 2 As shown in the SEM images of FIG. 2 , the clustered structure of nanocrystals was observed on the surface of the cluster, and the particle size distributions of the superparamagnetic nanocomposites were 305.9 โ 24.7 nm in Example 1 and 241.7 โ 20.1 nm in Example 2.
- the superparamagnetic nanocomposites of Examples 1 and 2 can be confirmed to have uniform size and particle size distribution.
- the size, distribution and surface zeta potential of the superparamagnetic nanocomposites of Examples 1 (state of the art) and 2 (invention) were measured using a Zetasizer (Nano ZS, available from Malvern) through dynamic light scattering particle size analysis.
- Tables 1 (state of the art) and 2 (invention) show the results of average hydrodynamic diameter, PDI and surface zeta potential of the superparamagnetic nanocomposites of Examples 1 (state of the art) and 2 (invention), respectively.
- FIG. 3 shows the results of measurement of the size of the superparamagnetic nanocomposite of Example 1 (state of the art)
- FIG. 4 shows the results of measurement of the zeta potential of the superparamagnetic nanocomposite of Example 1 (state of the art)
- FIG. 5 shows the results of measurement of the size of the superparamagnetic nanocomposite of Example 2 (invention)
- FIG. 3 shows the results of measurement of the size of the superparamagnetic nanocomposite of Example 1 (state of the art)
- FIG. 4 shows the results of measurement of the zeta potential of the superparamagnetic nanocomposite of Example 1 (state of the art)
- FIG. 5 shows the results of measurement of the size of the superparamagnetic nano
- Example 6 shows the results of measurement of the zeta potential of the superparamagnetic nanocomposite of Example 2 (invention).
- Table 1 - Example 1 Classification Size (nm) PDI Zeta potential (mV) 1 st Measurement 255.8 0.067 -15.4 2 nd Measurement 254.3 0.086 -15.0 3 rd Measurement 252.6 0.066 -15.0 Average 254.2 0.073 -15.1
- Table 2 - Example 2 Classification Size (nm) PDI Zeta potential (mV) 1 st Measurement 268.7 0.100 +24.3 2 nd Measurement 273.1 0.136 +25.7 3 rd Measurement 273.4 0.077 +26.0 Average 271.7 0.104 +25.3
- the superparamagnetic nanocomposites of Examples 1 and 2 were 0.073 and 0.104, falling in the range of less than 0.1 to about 0.1, corresponding to nearly monodisperse.
- the superparamagnetic nanocomposites of Examples 1 and 2 had a uniform size and particle size distribution.
- respective zeta potentials of the superparamagnetic nanocomposites of Examples 1 (state of the art) and 2 (invention) were -15.1 mV and +25.3 mV, falling in the zeta potential range of โ 10-30 mV, from which the superparamagnetic nanocomposite particles are evaluated to be efficiently dispersed through electrostatic repulsion.
- the superparamagnetic nanocomposites of Example 2 was stabilized by the carboxylate (COO - ) group, and thus had a zeta potential of +10-30 mV, thereby exhibiting high dispersibility in an aqueous solution.
- FIGS. 7 (state of the art) and 8 (invention) show the magnetic hysteresis loops of the superparamagnetic nanocomposite of the invention, as the result of measurement of magnetism.
- Example 1 state of the art
- 2 invention
- a ferromagnetic material is unsuitable for use in magnetic nanoparticle-mediated isolation technology because clustering of particles may strongly occur when a ferromagnetic material, having high residual magnetization, is repeatedly subjected to an external magnetic field.
- it is typically difficult to maintain the superparamagnetism of magnetic materials at room temperature.
- superpara-ferromagnetism transition occurs readily depending on how efficiently single domains are adjusted, regardless of the structures of magnetic materials or magnetic composites.
- the superparamagnetic nanocomposites of Examples 1 and 2 according to the present invention are configured such that tens of thousands of superparamagnetic nanocrystals are clustered, a final cluster, that is, a superparamagnetic nanocomposite having a diameter of 200 to 300 nm does not cause ferromagnetism transition, but superparamagnetism thereof is efficiently maintained.
- the superparamagnetic nanocomposites of Examples 1 and 2 according to the present invention have high magnetization and thus high separation capability suitable for use in magnetic separation.
- an anti-RBC antibody Fitzgerald, Human RBC antibody, Cat# 20R-RR006
- EDC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
- S N-hydroxysulfosuccinimide
- a PBS (pH 7.4) containing 0.5 mg/25 โ L of the anti-RBC antibody-functionalized superparamagnetic nanocomposite was added to 25 โ L of a whole blood sample, reacted at room temperature for 5 min, and then subjected to magnetic separation, thus separating the anti-RBC antibody-functionalized superparamagnetic nanocomposite. Thereafter, the separated anti-RBC antibody-functionalized superparamagnetic nanocomposite and the supernatant were observed under a microscope to count the number of RBCs, and the RBC separation capability (%) was calculated based on Equation 1 below. The results are shown in FIG. 9 .
- FIG. 9 shows the tube photographs before and after separation of RBCs and the microscope images of the separated superparamagnetic nanocomposite and the supernatant.
- RBC separation capability % number of captured RBCs / number of captured RBCs + number of noncaptured RBCs โ 100
- the RBC separation capability of the superparamagnetic nanocomposite was calculated to be 99.5% based on Equation 1.
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KR101227090B1 (ko) * | 2011-05-16 | 2013-01-28 | ๊ฐ๋ฆ์์ฃผ๋ํ๊ต์ฐํํ๋ ฅ๋จ | ํ๋ผ์ดํธ ์๋ธ๋ง์ดํฌ๋ก ์ ์์ ์ ์กฐ๋ฐฉ๋ฒ |
KR101516345B1 (ko) | 2013-03-14 | 2015-05-04 | ๊ณ ์ผ๋ฐ์ด์ค๋น๋ ์ฃผ์ํ์ฌ | ์์ฑ๋๋ ธ์ ์ ์ ์กฐ๋ฐฉ๋ฒ ๋ฐ ์ด๋ฅผ ์ด์ฉํด ์ ์กฐ๋ ์์ฑ๋๋ ธ์ ์ |
JP2016526378A (ja) * | 2013-06-11 | 2016-09-05 | ในใชใผใจใ ใคใใใคใใฃใ ใใญใใใฃใบ ใซใณใใใผ | ใซใซใใญใทใซๅฎ่ฝๅ่ถ ๅธธ็ฃๆงใใใฏใฉในใฟใผใไฝฟ็จใใ็ฃๆฐๅ้ขๆนๆณ |
WO2016022503A1 (en) * | 2014-08-02 | 2016-02-11 | Nvigen, Inc. | Uniform nanocompositions, methods of making the same, and uses of the same |
KR101729687B1 (ko) * | 2016-08-19 | 2017-05-22 | ์ฃผ์ํ์ฌ ์๋ชจ๋ผ์ดํ์ฌ์ด์ธ์ค | ์ด์์์ฑ ๋๋ ธ๋ณตํฉ์ฒด์ ์ ์กฐ๋ฐฉ๋ฒ ๋ฐ ์ด๋ฅผ ์ด์ฉํ์ฌ ์ ์กฐ๋ ์ด์์์ฑ ๋๋ ธ๋ณตํฉ์ฒด |
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JIA LIU ET AL: "Highly Water-Dispersible Biocompatible Magnetite Particles with Low Cytotoxicity Stabilized by Citrate Groups (Supporting Information)", ANGEWANDTE CHEMIE, 1 January 2009 (2009-01-01), pages 17pp, XP055692041, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002/ange.200901566&file=ange_200901566_sm_miscellaneous_information.pdf> [retrieved on 20200506] * |
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Publication number | Publication date |
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CN108496231A (zh) | 2018-09-04 |
KR101729687B1 (ko) | 2017-05-22 |
CN108496231B (zh) | 2021-07-30 |
WO2018034464A1 (ko) | 2018-02-22 |
US20180254130A1 (en) | 2018-09-06 |
JP2019509975A (ja) | 2019-04-11 |
US10658097B2 (en) | 2020-05-19 |
US11087908B2 (en) | 2021-08-10 |
EP3389062A1 (en) | 2018-10-17 |
EP3389062A4 (en) | 2019-01-23 |
JP6788686B2 (ja) | 2020-11-25 |
US20200265978A1 (en) | 2020-08-20 |
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